1. Field of the Invention
The present invention relates to methods for treating ovarian cancer, in particular those pertaining to the extended release of an antineoplastic agent from biodegradable poly(phosphoester) compositions.
2. Description of the Prior Art
Antineoplastic agents, such as paclitaxel, have sometimes been used to treat ovarian cancer. For example, those in the art have attempted to administer paclitaxel in normal saline by infusion into the peritoneal cavity of women having ovarian cancer as a prolonged series of weekly treatments. Francis et al., xe2x80x9cPhase I Feasibility and Pharmacologic Study of Weekly Intraperitoneal Paclitaxel: A Gynecologic Oncology Group Pilot Studyxe2x80x9d, J. of Clinical Oncology, 13:12, 2961-67 (1995). However, problems with multiple toxicities, such as abdominal pain, nausea, vomiting, leukopenia, and fatigue, are often encountered with the high fluid volumes and drug dosages required for efficacy with this approach. Further, the repeated dosing and attendant discomfort is often inconvenient and, sometimes, even unacceptable for patients.
Thus, there exists a need for a method of effecting the in vivo, controlled release of a variety of different antineoplastic agents into the peritoneum, whether they are small hydrophobic drugs, such as paclitaxel, or large and bulky bio-macromolecules, such as therapeutically useful proteins. Preferably, effective release of the antineoplastic agent should occur without requiring the presence of significant amounts of a physiologically acceptable fluid vehicle, such as normal saline or an organic solvent. There is also a continuing need for biodegradable polymer compositions that may provide extended release in such a way that trauma to the surrounding soft tissues can be minimized.
Biocompatible polymeric materials have been used in various therapeutic drug delivery and medical implant applications. If a medical implant is intended for use as a drug delivery or other controlled-release system, using a biodegradable polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., xe2x80x9cChemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agentsxe2x80x9d, J. Macro. Science, Rev. Macro. Chem. Phys., C23(1), 61-126 (1983). In this way, less total drug is required, and toxic side effects can be minimized.
Polymers have been used for some time as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., xe2x80x9cPolymeric Controlled Drug Deliveryxe2x80x9d, Advanced Drug Delivery Rev., 1:199-233 (1987); Langer, xe2x80x9cNew Methods of Drug Deliveryxe2x80x9d, Science, 249:1527-33 (1990) and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., xe2x80x9cBiodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonistsxe2x80x9d, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. xe2x80x9cTrends in the Development of Bioresorbable Polymers for Medical Applicationsxe2x80x9d, J. Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., xe2x80x9cBiodegradable Lysine Diisocyanate-based Poly(Glycolide-co-xcex5 Caprolactone)-Urethane Network in Artificial Skinxe2x80x9d, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., xe2x80x9cRelease of Norethindrone from Poly(Ortho Esters)xe2x80x9d, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., xe2x80x9cPolyanhydrides for Controlled Release of Bioactive Agentsxe2x80x9d, Biomaterials 7:5, 364-71 (1986).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: xe2x80x9cPhosphorus-Containing Polymersxe2x80x9d, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or Rxe2x80x2 group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with -O-carboxy groups may be coupled to the phosphorus via a phosphoester bond, which is hydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. The Pxe2x80x94Oxe2x80x94C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
Copending U.S. application Ser. No. 09/053,648 and WO 98/44021 disclose biodegradable terephthalate polyester-poly(phosphate) compositions; U.S. application Ser. No. 09/053,649 and WO 98/44020 disclose biodegradable compositions containing polymers chain-extended by phosphoesters; and U.S. application Ser. No. 09/070,204 and International Application No. PCT/U.S. Pat. No. 98/09185 disclose biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds. However, none of these disclosures suggests the specific use of biodegradable poly(phosphoester) compositions for treating ovarian cancer specifically.
Thus, there remains a need for new methods and materials for the difficult problem of successfully treating ovarian cancer with a minimum of discomfort, toxicities and prolonged, periodic re-dosing.
It has now been discovered that biodegradable polymer compositions comprising:
(a) at least one antineoplastic agent and
(b) a biodegradable polymer comprising the recurring monomeric units shown in formula I: 
wherein
X is xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94, where R4 is H or alkyl;
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR4xe2x80x94;
each of R1 and R2 is a divalent organic moiety;
L is a divalent, branched or straight chain aliphatic group having 1-20 carbon atom, a cycloaliphatic group, or a group having the formula: 
R3 is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and
n is about 5-5,000;
are suitable for intraperitoneal administration to treat a mammalian subject having ovarian cancer. These polymer compositions provide extended release of the antineoplastic agent within the peritoneum of the subject. Moreover, the polymer composition of the invention increases the median survival rate from the cancer by at least about 10%, as compared with the median survival rate obtained by administration of a composition comprising the same dosage of the antineoplastic agent without the biodegradable polymer of the invention.
The invention also comprises a solid article suitable for insertion into the peritoneum to treat a mammalian subject having ovarian cancer, the article comprising a biodegradable polymer composition comprising:
(a) at least one antineoplastic agent and
(b) a biodegradable polymer comprising the recurring monomeric units shown above in formula I.
In yet another embodiment of the invention, a method is provided for treating a mammalian subject having ovarian cancer by the extended release of an antineoplastic agent, the method comprising the steps of:
(a) combining the antineoplastic agent with a biodegradable polymer having the recurring monomeric units shown above in formula I to form a composition; and
(b) inserting the composition in vivo into the peritoneum of the subject, such that the inserted composition is in at least partial contact with an ovarian cancer tumor,
wherein the median survival rate from the cancer is increased by at least about 10%, as compared with the median survival rate obtained by administration of a composition comprising the same dosage of the antineoplastic agent without the biodegradable polymer.
The compositions of the invention can be used to deliver a wide variety of antineoplastic agents, for example, from hydrophobic drugs, such as paclitaxel, to large water-soluble macromolecules, such as proteins, over an extended period of time without necessitating significant volumes of a delivery fluid. The methods of the invention can thus be used to significantly increase the time period over which an effective dose of the antineoplastic agent is released and increases the survival time of subjects treated by the method to an unexpected degree. Further, the serious disease of ovarian cancer can be therapeutically managed with a minimum of side effects and without the unpleasantness and discomfort of a periodic series of parenteral treatments introducing significant amounts of fluid into the peritoneum.